Microglia and TREM2
Jennifer Pocock1, Foteini Vasilopoulou1, Elina Svensson1
1Department of Neuroinflammation, And Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N1PJ, UK.
Abstract:
TREM2 is a membrane receptor solely expressed on microglia in normal brain. In this review we outline recent advances in TREM2 biology and its implications for microglial function, with particular emphasis on findings from iPSC-derived microglia (iMG) expressing TREM2 loss-of-function mutations. Alterations in receptor proximal and distal signalling underlie TREM2 risk variants linked to neurodegenerative disease, principally NH-linked FTD, and late-onset AD, but emerging data suggest roles for TREM2 in PD, MS and ALS. TREM2 downstream functions include phagocytosis of myelin debris, amyloid beta peptides, and phosphatidylserine-expressing cells (resulting from damage or stress). Microglial survival, migration, DAMP signalling, inflammasome activation, and intercellular signalling including tau spreading via exosomes, as well as roles for sTREM2 in protection and as a biomarker are discussed. The role of TREM2 in metabolic homeostasis, and immunometabolic switching are discussed regarding microglial responses to damage and protection. The use of iPSC models to investigate the role of TREM2 in AD, PD, MS, ALS, and other neurodegenerative diseases could prove invaluable due to their ability to recapitulate human pathology, allowing a full understanding of TREM2 and microglial involvement in the underlying disease mechanisms and progression. This article is part of the Special Issue on "Microglia".
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function in the brain. Research highlights TREM2's role in neurodegenerative diseases like Alzheimer's and Parkinson's, using iPSC models to understand its mechanisms.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Neurodegenerative Disease Research
Background:
- TREM2 is a microglial receptor critical for brain homeostasis.
- TREM2 dysfunction is linked to neurodegenerative diseases, including Alzheimer's and FTD.
- iPSC-derived microglia (iMG) offer a model to study TREM2 in human disease.
Purpose of the Study:
- To review recent advances in TREM2 biology and its impact on microglial function.
- To emphasize findings from iPSC-derived microglia with TREM2 loss-of-function mutations.
- To explore TREM2's role in various neurodegenerative conditions.
Main Methods:
- Review of current literature on TREM2 biology and signaling.
- Analysis of data from iPSC-derived microglia (iMG) models.
- Discussion of TREM2's downstream functions and clinical relevance.
Main Results:
- TREM2 signaling alterations are associated with risk variants for FTD and AD.
- TREM2 mediates microglial phagocytosis of debris, amyloid peptides, and stressed cells.
- TREM2 influences microglial survival, migration, and inflammatory responses.
Conclusions:
- TREM2 plays a multifaceted role in microglial responses to damage and in neuroprotection.
- iPSC models are invaluable for dissecting TREM2's contribution to neurodegenerative disease mechanisms.
- Understanding TREM2 is key to developing therapies for AD, PD, MS, and ALS.
